Chronic alcoholic liver disease (ALD) progresses through stages of steatohepatitis, fibrosis, cirrhosis, and finally end-stage liver disease, which culminates in liver failure. ALD is common, and accounts for 28% of all deaths from liver disease in the USA. Moreover, ALD either additively or synergistically contributes to liver failure in patients with chronic hepatitis B or C viral infections. While the toxic effects of ethanol and ts metabolites promote liver injury and cell death, the long-term adverse effects of ethanol on hepatocellular growth, survival, energy metabolism, and gene expression, are attributable to impairments in signal transduction pathways driven by insulin and IGF stimulation. The resulting state of hepatic insulin/IGF resistance is, in large measure, responsible for ethanol-mediated impairments in liver regeneration and repair following injury. Importantly, recent evidence suggests that an even larger network of inter-related signaling pathways mediate hepatocellular growth, repair and regeneration, and that restoration of liver function in chronic ALD may require, or to be optimized by increasing support of the network rather than a single component. In this regard, we have detected significant inhibition of Wnt pathway genes in livers of chronic ethanol-fed experimental animals, and in human alcoholics. Furthermore, evidence suggests that the Wnt and insulin/IGF pathways cross-talk in regulating liver growth, repair, and regeneration. Since the lists of Wnt signaling mediators and insulin sensitizer agents continue to grow, in the near future, it may be feasible to restore liver function in chronic ALD by treatment with insulin sensitizers, Wnt agonists, or both. Given the multiple potential side-effects of insuln sensitizer agents, advancing knowledge that leads to increased availability of scientifically-based alternative therapeutic measures for targeting ALD would be advantageous. The proposed studies will examine the role of reduced Wnt signaling and inhibition of Wnt cross-talk with insulin/IGF pathway as mechanisms of impaired hepatocellular growth and repair in chronic ALD. Aim 1 will characterize effects of chronic ethanol exposure on Wnt signaling, and correlate abnormalities with impairments in DNA synthesis in liver in established in vivo and ex vivo models. Aim 2 is to characterize the effects of chronic ethanol exposure on IGF1-Wnt crosstalk in liver. We will demonstrate how ethanol-impaired IGF1 signaling leads to inhibition of the Wnt/-catenin pathway, determine the degree to which inhibition of Wnt impairs IGF1 signaling, and finally characterize potential mechanisms of IGF-Wnt cross-talk in liver, focusing on the role of GSK-3 and the destruction complex. The proposed studies may determine new molecular mechanisms by which chronic ethanol consumption impairs liver regeneration via cross-talk between two important signaling pathways, i.e., insulin/IGF and Wnt. Moreover, the results from these investigations could identify novel therapeutic targets for treating chronic ALD, including restoration of liver function following bouts of injury. PUBLIC HEALTH RELEVANCE: Chronic alcoholic liver disease (ALD) causes liver failure and death due to impaired capacity of the liver to repair and regenerate. Hepatocellular growth is mediated by insulin/IGF and Wnt signaling, and preliminary studies showed that, in addition to its inhibitory effects on insulin/IGF pathways, ethanol profoundly impairs Wnt and Wnt target gene expression in liver. The proposed research is designed to characterize the mechanisms of Wnt-Insulin/IGF crosstalk, and demonstrate how ethanol disrupts this critical network in the context of chronic ALD.